The present invention relates to 3-methyl-chromane or thiochromane derivatives having anti-estrogenic activity. More specifically, the present invention relates to 3-methyl-chromane or thiochromane derivatives represented by the following formula (1): 
in which
X represents O or S,
R1 represents hydrogen or metal, and
m represents an integer of 2 to 14, pharmaceutically acceptable salts, stereoisomers or hydrates thereof, and an anti-estrogenic pharmaceutical composition which comprises the compound of formula (1) as an active component.
In treating diseases that are dependent upon a certain sexual hormone such as estrogen, it is important to significantly reduce or inhibit the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the receptor site stimulated by sexual steroidal hormone. For instance, hysterectomy may be applied to limit the production of estrogen to the amount less than required to activate the receptor site. However, this method could not sufficiently inhibit the effect induced through the estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. Accordingly, it was considered that antagonists for estrogen can provide better therapeutic effect in comparison to the method for blocking only the production of sexual steroidal hormone (see, WO 96/26201). Thus, numerous anti-estrogenic compounds have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 and WO 96/22092, etc. disclose various anti-estrogenic compounds. Sometimes, however, prior antagonists may act themselves as agonists, and therefore, activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, it has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertil., 1967, 13, 101).
As another non-steroidal anti-estrogenic compound, WO 93/10741 discloses a benzopyran derivative having aminoethoxyphenyl substituent (Endorecherche), the typical compound of which is EM-343 having the following structure: 
Said compound also has the agonistic effect. Therefore, it is required to develop an anti-estrogenic compound which has substantially or completely no agonistic effect and can effectively block the estrogenic receptor.
In addition, it has been known that 7xcex1-substituted derivatives of estradiol, for example, 7xcex1-(CH2)10CONBuMe derivatives, are steroidal anti-estrogenic agent without agonistic effect (see, EP Appl. 0138504, U.S. Pat. No. 4,659,516). Further, estradiol derivative having 7xcex1-(CH2)9SOC5H6F5 substituent has also been disclosed (see, Wakeling et al., Cancer Res., 1991, 51, 3867).
Non-steroidal anti-estrogenic drug without agonistic effect has been first reported by Wakeling et al. in 1987 (see, A. Wakeling and J. Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 (ICI, Great Britain) discloses a phenol derivative having anti-estrogenic activity. This phenol derivative mainly has a tetrahydronaphthalene structure and includes, typically, the following compounds: 
in which R1, R2, n, p and q are defined as described in the prior arts as mentioned above.
Some chromane and thiochromane derivatives have been reported as anti-estrogenic compounds having no agonistic effect (WO 98/25916). Although the existing anti-estrogenic compounds having no agonistic effect show a substantial therapeutic effect when administered via intravenous or subcutaneous injection, they show little therapeutic activity when administered orally, which is considered to be caused by several factors, one of which is the low bioavailability. Therefore, for convenience"" sake in the case of administration, it is desired to develop anti-estrogenic compounds which show a sufficient effect when administered orally and at the same time have no agonistic effect.
Under these technical backgrounds, the present inventors have screened the anti-estrogenic activity of the new compounds having various structures. As a result, we have identified that 3-methyl-chromane or thiochromane derivatives represented by the following formula (1) can exhibit a good anti-estrogenic activity with no substantial agonistic effect even when orally administered, whereby we completed the present invention.
Therefore, the present invention relates to 3-methyl-chromane or thiochromane derivatives represented by the following formula (1): 
in which
X represents O or S,
R1 represents hydrogen or metal, and
m represents an integer of 2 to 14, pharmaceutically acceptable salts, stereoisomers or hydrates thereof.
It is another object of the present invention to provide a medicine, more specifically an anti-estrogenic pharmaceutical composition which comprises the compound of formula (1) as an active component together with pharmaceutically acceptable carriers.
In the compound of formula (1) according to the present invention, when R1 is metal, R1 may include alkali metals such as sodium, potassium, etc.; alkaline earth metals such as magnesium, calcium, etc.; rare earth metals such as cerium, samarium, etc.; and zinc, tin, etc. Among them, alkali metals and alkaline earth metals are more preferable, and alkali metals (particularly, sodium) are most preferable. When R1 is a monovalent metal such as an alkali metal, the R1 group combines with the residue of the compound of formula (1) in a ratio of 1:1. However, when R1 is other than the monovalent metal, it combines in a ratio of more than 1:1 depending on the valency of the metal.
The compound of formula (1) according to the present invention can exist as a stereoisomer, and thus, the present invention also includes each of the stereoisomers and their mixtures including racemate. Among the stereoisomers, compounds wherein the configuration of 3- and 4-position chiral carbons in the chromane(or thiochromane) ring is (3R, 4R) or (3S, 4S) or mixtures thereof are preferable, and in this case, compounds wherein the chiral carbon in the 4-position side chain of chromane(or thiochromane) ring, to which R1OOCxe2x80x94 group is attached, has the configuration of R or S or mixtures thereof are preferable.
As the pharmaceutically acceptable salts of the compound of formula (1), the metal salts as described above, for example, sodium, potassium, calcium salt, etc. can be mentioned. These salts may be prepared according to the conventional conversion methods.
Among the compound of formula (1), the preferred compounds include those wherein R1 is hydrogen, X is oxygen or sulfur, and m is an integer of 6 to 10, particularly preferably an integer of 8 or 9.
As typical examples of the compound of formula (1), the following compounds can be mentioned:
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoic acid; and
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoic acid.
The compound of formula (1) according to the present invention can be prepared by the following Processes I to V, and thus, the present invention also provides these processes.
(Process I)
The compound of formula (1) can be prepared by a process characterized in that
(a) a compound of the following formula (2): 
xe2x80x83in which
X is defined as previously described, and
R11 represents hydroxy- or carboxy-protecting group, preferably t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, t-butyldiphenylsilyl, methoxymethyl, tetrahydropyranyl, methyl, ethyl, etc., is reacted with an acetylene compound of the following formula (3):
HCxe2x89xa1Cxe2x80x94(CH2)m1OR12xe2x80x83xe2x80x83(3).
xe2x80x83in which
m1 represents a number of m-2, and
R12 represents hydroxy- or carboxy-protecting group, preferably t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, t-butyldiphenylsilyl, methoxymethyl, tetrahydropyranyl, methyl, ethyl, etc., in an inert solvent in the presence of a base to give a compound of the following formula (4): 
in which X, m1, R11 and R12 are defined as previously described (where tetrahydrofuran, dioxane, dichloromethane or chloroform, preferably tetrahydrofuran or dioxane is used as the inert solvent; n-butyllithium, sec-butyllithium or sodium hydride is used as the base; and the reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to room temperature);
(b) the compound of formula (4) is reduced by sodium cyanoborohydride in an inert solvent in the presence of a Lewis acid to give a compound of the following formula (5): 
in which X, m1, R11 and R12 are defined as previously described (where tetrahydrofuran, dioxane, dichloromethane, dichloroethane, or chloroform, preferably dichloroethane is used as the inert solvent; zinc iodide is used as the Lewis acid; and the reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature);
(c) the compound of formula (5) is subjected to a catalytic hydrogenation reaction in an inert solvent and optionally in the presence of sodium hydrogen carbonate to give a compound of the following formula (6): 
in which X, m, R11 and R12 are defined as previously described (where methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, or chloroform, preferably tetrahydrofuran or ethyl acetate is used as the inert solvent; activated Pd/C, palladium hydroxide or platinum oxide is used as the catalyst; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature), however, the compound of formula (6) may be directly obtained from the compound of formula (4) through a catalytic hydrogenation reaction in an inert solvent (where the reaction conditions are the same as the step of preparing the compound of formula (6) from the compound of formula (5));
(d) the hydroxy group in the compound of formula (6) is deprotected by the treatment with one or more substances selected from a group consisting of tetrabutylammonium fluoride, cesium fluoride, hydrofluoride-pyridine, hydrochloride, sulfuric acid and p-toluenesulfonic acid in an inert solvent to give a compound of the following formula (7): 
in which X, m, and R11 are defined as previously described (where tetrahydrofuran, dioxane, dichloromethane, dichloroethane, or chloroform, preferably tetrahydrofuran is used as the inert solvent; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture);
(e) the compound of formula (7) is treated with methyl sulfonyl chloride or p-toluene sulfonyl chloride in an inert solvent in the presence of an organic base to convert the group of (CH2)mOH in compound (7) to a group of (CH2)mOxe2x80x94SO2CH3 or (CH2)mOxe2x80x94SO2xe2x80x94C6H4-p-CH3 (where tetrahydrofuran, dioxane, dichloromethane, dichloroethane, or chloroform, preferably dichloromethane is used as the inert solvent; triethylamine or pyridine is used as the organic base; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature), or the resulting compound is further treated with metal halide in an inert solvent to give a compound of the following formula (8): 
xe2x80x83in which
X, m, and R11 are defined as previously described, and
L1 represents a leaving group, preferably methanesulfonyloxy, p-toluenesulfonyloxy, halogen, etc. (where acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably dichloromethane is used as the inert solvent; sodium iodide or potassium iodide is used as the metal halide; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture);
(f) the compound of formula (8) is reacted with a malonate of the following formula (9): 
xe2x80x83in which
R13 represents hydroxy- or carboxy-protecting group, preferably t-butydimethylsilyl, triisopropylsilyl, triethylsilyl, t-butyldiphenylsilyl, methoxyrethyl, tetrahydropyranyl, methyl, ethyl, etc., in an inert solvent in the presence of a base to give a compound of the following formula (10): 
in which X, m, R11 and R13 are defined as previously described (where tetrahydrofuran, dioxane, dimethylsulfoxide, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran is used as the inert solvent; sodium hydride, sodium hydroxide or potassium t-butoxide is used as the base; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture);
(g) the compound of formula (10) is reacted with a compound of the following formula (11):
CF3CF2(CH2)6xe2x80x94L2xe2x80x83xe2x80x83(11).
in which L2 represents a leaving group, preferably methanesulfonyloxy, p-toluenesulfonyloxy, halogen, etc., in an inert solvent in the presence of a base to give a compound of the following formula (12): 
in which X, m, R11 and R13 are defined as previously described (where the reaction conditions are the same as step (f));
(h) the compound of formula (12) is treated with sodium hydroxide or potassium hydroxide in an inert solvent to give a compound of the following formula (13): 
in which X, m and R11 are defined as previously described (where water, ethanol, methanol, water-ethanol or water-methanol mixture is used as the inert solvent; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture);
(i) the compound of formula (13) is heated to a temperature of from 50xc2x0 C. to the boiling point of the reaction mixture in an inert solvent and optionally in the presence of an acid to give a compound of the following formula (14): 
in which X, m and R11 are defined as previously described (where dimethylsulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran is used as the inert solvent; and hydrochloric acid, sulfuric acid or p-toluenesulfonic acid is used as the acid); and
(j) the compound of formula (14) is deprotected by an acid to give a compound of the following formula (1a): 
in which X and m are defined as previously described (where hydrochloric acid, sulfuric acid, hydrobromic acid, hydrogen pyridinium chloride or borontribromide is used as the acid; and the reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture); or
(k) the compound of formula (1a) is treated with a compound of the following formula (15):
xe2x80x83R1xe2x80x2xe2x80x94L3xe2x80x83xe2x80x83(15).
xe2x80x83in which
R1xe2x80x2 represents a metal, and
L3 represents hydroxy, alkylcarbonyloxy, lower alkoxy, etc., to give a metal salt compound of the following formula (1b): 
in which X, m and R1xe2x80x2 are defined as previously described.
(Process II)
The compound of formula (1) can also be prepared by a process characterized in that the compound of formula (13) obtained in step (h) of Process I is reacted according to the same procedure as step (j) to give a compound of the following formula (16): 
in which X and m are defined as previously described, the resulting compound (16) is reacted according to the same procedure as step (i) to give the compound of formula (1a), which may be further converted to a metal salt thereof according to the same procedure as step (k) to give the compound of formula (1b). That is, Process II produces the compound of formula (1) in the same manner as Process I except that the order of decarboxylation and deprotection of group R11 is reversed. And the reaction conditions are the same.
(Process III)
The compound of formula (1) can also be prepared by a process characterized in that the compound of formula (8) obtained in step (e) of Process I is reacted with a compound of the following formula (17): 
in which R13 is defined as previously described, in an inert solvent in the presence of a base to give the compound of formula (12) (where tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran is used as the inert solvent; sodium hydride, sodium hydroxide or potassium t-butoxide is used as the base; and the reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture) and the subsequent reactions are carried out according to the same procedure as Process I or II.
(Process IV)
The compound of formula (1) can also be prepared by a process characterized in that
(a) a compound of the following formula (18): 
xe2x80x83in which
X and R11 are defined as previously described, and
m2+m3+2 equals m, is reacted with a compound of the following formula (19): 
in which m3 and R13 are defined as previously described, in an inert solvent in the presence of a catalyst to give a compound of the following formula (20): 
in which X, R11, R13, m2 and m3 are defined as previously described (where methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide is used as the inert solvent; benzylidene-bis(tricyclohexylphosphine)dichlororuthenium is used as the catalyst; and the reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture); and
(b) the compound of formula (20) is subjected to a catalytic hydrogenation reaction in an inert solvent to give a compound of the following formula (21): 
in which X, m, R11 and R13 are defined as previously described (where methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene is used as the inert solvent; activated Pd/C, palladium hydroxide, platinum oxide or Wilkinson""s catalyst is used as the catalyst; and the reaction is carried out at temperatures ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature) ), and then hydrolysis, deprotection and conversion to the metal salt thereof are carried out according to the same procedure as Process I or II.
(Process V)
The compound of formula (1) can also be prepared by a process characterized in that
(a) the compound of formula (18) is reacted with a compound of the following formula (22): 
in which R13 and m3 are defined as previously described, in an inert solvent in the presence of a catalyst to give a compound of the following formula (23): 
in which X, R11, R13, m2 and m3 are defined as previously described (where the reaction conditions are the same as step (a) of Process IV); and
(b) the compound of formula (23) is subjected to a catalytic hydrogenation reaction in a solvent to give a compound of the following formula (24): 
in which X, R11, R13 and m are defined as previously described (where the reaction conditions are the same as step (b) of Process IV), and then hydrolysis, decarboxylation, deprotection and conversion to the metal salt thereof are carried out according to the same procedure as Process I or II.
The compound of formula (1) thus prepared may be separated and purified using the conventional methods, such as for example, column chromatography, recrystallization, etc.
The above processes I to V according to the present invention will be more specifically explained through the following examples.
As stated above, the compound of formula (1) prepared according to the processes as explained above has a good anti-estrogenic activity and therefore, can be used for the treatment of estrogen-related diseases including anovular infertility, breast cancer, endometrial cancer, uterine cancer, ovarian cancer, endometriosis, endometrial fibroma, benign prostate hypertrophy, premature, menstrual disorder, etc.
Therefore, the present invention relates to an anti-estrogenic pharmaceutical composition comprising the compound of formula (1) as an active component together with pharmaceutically acceptable carriers.
When the anti-estrogenic pharmaceutical composition containing the compound of the present invention as an active component is used for clinical purpose, it can be formulated into a conventional preparation in the pharmaceutical field, for example, preparation for oral administration such as tablet, capsule, troche, solution, suspension, etc., or injectable preparation such as injectable solution or suspension, ready-to-use injectable dry powder which can be reconstituted with distilled water for injection when it is injected, etc., by combining with carriers conventionally used in the pharmaceutical field.
Suitable carrier which can be used in the composition of the present invention includes those conventionally used in the pharmaceutical field, for example, binder, lubricant, disintegrant, excipient, solubilizer, dispersing agent, stabilizing agent, suspending agent, coloring agent, perfume, etc. for oral preparation; and preservative, pain alleviating agent, solubilizing agent, stabilizing agent, etc. for injectable preparation. The pharmaceutical preparation thus prepared can be administered orally or parenterally, for example, intravenously, subcutaneously or intraperitoneally. In addition, in order to prevent the active component from being decomposed with gastric acid, the oral preparation can be administered together with an antacid or in the enteric-coated form of the solid preparation such as tablet.
The dosage of the 3-methyl-chromane or thiochromane derivative of formula (1) for human being can be suitably determined depending on absorption, inactivation and secretion of the active ingredient in the human body, age, sex and condition of subject patient, severity of the disease to be treated. It is generally suitable to administer the compound of formula (1) in an amount of 0.1 to 500 mg/day when it is orally administered, and in an amount of 1 to 1000 mg/month when it is parenterally administered (intravenous, intramuscular, or subcutaneous injection) for adult patient.
The present invention is more specifically explained by the following examples. However, it should be understood that the present invention is not limited to these examples in any manner.